Structure-activity relationship in NOD2 agonistic muramyl dipeptides.

Nucleotide-binding oligomerization domain 2 (NOD2) is a receptor of the innate immune system that is capable of perceiving bacterial and viral infections. Muramyl dipeptide (MDP, N-acetyl muramyl L-alanyl-d-isoglutamine), identified as the minimal immunologically active component of bacterial cell wall peptidoglycan (PGN) is recognized by NOD2. In terms of biological activities, MDP demonstrated vaccine adjuvant activity and stimulated non-specific protection against bacterial, viral, and parasitic infections and cancer. However, MDP has certain drawbacks including pyrogenicity, rapid elimination, and lack of oral bioavailability. Several detailed structure-activity relationship (SAR) studies around MDP scaffolds are being carried out to identify better NOD2 ligands. The present review elaborates a comprehensive SAR summarizing structural aspects of MDP derivatives in relation to NOD2 agonistic activity.

Structure-Activity Relationships toward the Identification of a High-Potency Selective Human Toll-like Receptor-7 Agonist.

Toll-like receptor (TLR)-7 agonists are immunostimulatory vaccine adjuvants. A systematic structure-activity relationship (SAR) study of TLR7-active 1-benzyl-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine led to the identification of a potent hTLR7-specific p-hydroxymethyl IMDQ 23 with an EC50 value of 0.22 µM. The SAR investigation also resulted in the identification of TLR7 selective carboxamide 12 with EC50 values of 0.32 µM for hTLR7 and 18.25 µM for hTLR8. In the vaccination study, TLR7-specific compound 23 alone or combined with alum (aluminum hydroxide wet gel) showed adjuvant activity for a spike protein immunogen in mice, with enhanced anti-spike antibody production. Interestingly, the adjuvant system comprising carboxamide 12 and alum showed prominent adjuvant activity with high levels of IgG1, IgG2b, and IgG2c in immunized mice, confirming a balanced Th1/Th2 response. In the absence of any apparent toxicity, the TLR7 selective agonists in combination with alum may make a suitable vaccine adjuvant.

A Comparative Evaluation of Push-Out Bond Strength of Six Different Root Canal Sealers: An In-Vitro Study.

BACKGROUND: Adhesiveness with radicular dentin is absent with gutta-percha, leading to microleakage and hence re-infection. Root canal sealer helps to achieve an adhesive interface between gutta-percha and root dentin thereby resisting the displacement forces during the functioning of teeth which is evaluated by the push-out test. The aim of this study is to compare the push-out bond strength and to assess the relative bond failure between dentin-sealer, sealer-main cone of (1) epoxy resin, (2) silicon, (3) mineral trioxide aggregate (MTA), (4) calcium hydroxide, (5) bioceramic, (6) zinc oxide eugenol containing root canal sealers. METHODOLOGY: Sixty human permanent lower premolars with one root were collected, disinfected, and decoronated at cemento-enamel junction. Instrumentation was done with a K3 40,0.06 Ni-Ti rotary file and obturated using the main cone and sealer. Based on the sealer utilized, six groups were created: Group 1: AH-Plus, Group 2: RoekoSeal, Group 3: MTA Fillapex, Group 4: Apexit, Group 5: Smart Paste Bio, and Group 6: Procosol. One slice each was obtained from the coronal, middle, and apicalsections of all the obturated canals. Push-out bond strength and failure modes were studied. Statistics involved analysis of variance (ANOVA) followed by the post hoc Tukey test. RESULTS: All three sections exhibited the highest strength for Smart Paste Bio sealer and the least was for RoekoSeal. With all the sealers, the apical section had the highest strength followed by the middle and coronal. CONCLUSION: The smart seal system was superior to all other sealers and displayed a good bond to dentin.

Comparative evaluation of clinical success of Stainless Steel and Bioflx crowns in primary molar - A 12 month split mouth prospective randomized clinical trial.

PURPOSE: The purpose of this clinical trial was to assess and compare the clinical outcomes of Bioflx crowns (BFCs) with stainless steel crowns (SSCs) in primary molars (PMs). MATERIALS AND METHODS: This prospective split-mouth randomized controlled clinical trial was conducted between March 2022 and June 2023. Thirty-eight patients (17 females and 21 males) with a mean age of 5.21 years participated in this study. Each child (n = 38) received both SSC and BFC. Clinical and radiographic follow-up was performed at baseline, 3, 6, and 12 months using the modified United States Public Health System scoring criteria to evaluate various parameters. RESULTS: At the 3 and 6 months' follow-up, no significant difference was observed between the two groups. However, at 1-year follow-up, a statistically significant difference (P < 0.05) was evident in the frequency between the two groups for the criteria of crown retention after cementation and anatomic form of the crown, indicating a preference for SSC over prototype 1 BFC. CONCLUSION: The 12-month results indicate that BFC performed similarly to the established SSC for the restoration of PMs providing better esthetics.

Best Practice Recommendations for Infertility Management.

Aim: The objective of this document is to provide guidance to the infertility specialist, gynecologist, embryologist, and counselors on the management of sub-fertility and brief them with the recent advances in the field. These recommendations will aid the aforementioned healthcare professionals in everyday clinical decisions about appropriate and effective care of their patients with the best available evidence. Participants: Extensive deliberations, discussion, and brainstorming was done between different reproductive medicine (RM) specialists, to develop the recommendations. Evidence: A systematic review of the literature published up to June 2019 was carried out using PubMed and Cochrane Collaboration Library. International guidelines, cohort studies, case series, observational studies, and randomized controlled trials currently available in the literature were reviewed. Indian data whatever available was also reviewed. Process: Primary meetings were held with leading reproductive medicine specialists. Each topic was brainstormed on by a group of reproductive medicine experts, who then prepared the first draft of the recommendation. These recommendations then were reviewed by Dr. Jaideep Malhotra, Dr. Gouri Devi, and Dr. Madhuri Patil along with the chief co-ordinator of each consensus to finalize the final draft. Conclusions: From the literature and discussion of the available evidence, several topics were identified for which evidence is inconsistent, insufficient, or non-existing. For the benefit of couples undergoing several treatments, the working committee recommends that future research, where possible in well-designed RCTs, will help in establishing evidence for a particular practice. In the Indian context, one also needs to take into consideration facilities and options available, cost, lack of insurance coverage, experimental nature of some advanced techniques used.

Imidazo[1,2-a]pyrimidine as a New Antileishmanial Pharmacophore against Leishmania amazonensis Promastigotes and Amastigotes.

Leishmania poses a substantial threat to the human population all over the globe because of its visceral and cutaneous spread engendered by all 20 species. Unfortunately, the available drugs against leishmania are already hobbled with toxicity, prolonged treatment, and increasing instances of acquirement of resistance. Under these grave circumstances, the development of new drugs has become imperative to keep these harmful microbes at bay. To this end, a Groebke-Blackburn-Bienaymé multicomponent reaction-based library of different imidazo-fused heterocycles has been synthesized and screened against Leishmania amazonensis promastigotes and amastigotes. Among the library compounds, the imidazo-pyrimidine 24 has been found to be the most effective (inhibitory concentration of 50% (IC50) < 10 µM), with selective antileishmanial activity on amastigote forms, a stage of the parasite related to human disease. The compound 24 has exhibited an IC50 value of 6.63 µM, being ∼two times more active than miltefosine, a reference drug. Furthermore, this compound is >10 times more destructive to the intracellular parasites than host cells. The observed in vitro antileishmanial activity along with suitable in silico physicochemical and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of compound 24 reinforce the imidazo-pyrimidine scaffold as a new antileishmanial pharmacophore and encourage further murine experimental leishmaniasis studies.

Imidazo[2,1-b]thiazole based indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor: Structure based design, synthesis, bio-evaluation and docking studies.

Indoleamine-2,3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme known to catalyse the initial and rate limiting step of kynurenine pathway of l-tryptophan metabolism. IDO1 enzyme over expression plays a crucial role in progression of cancer, malaria, multiple sclerosis and other life-threatening diseases. Several efforts over the last two decades have been invested by the researchers for the discovery of different IDO1 inhibitors and the plasticity of the IDO1 enzyme ligand binding pocket provide ample opportunities to develop new heterocyclic scaffolds targeting this enzyme. In the present work, based on the X-ray crystal structure of human IDO1 coordinated with few ligands, we designed and synthesized new fused heterocyclic compounds and evaluated their potential human IDO1 inhibitory activity (compound 30 and 41 showed IC50 values of 23 and 13 µM, respectively). The identified HITs were observed to be non-toxic to HEK293 cells at 100 µM concentration. The observed activity of the synthesized compounds was correlated with the specific interactions of their structures at the enzyme pocket using docking studies. A detailed analysis of docking results of the synthesized analogues as well as selected known IDO1 inhibitors revealed that most of the inhibitors have some reasonable docking scores in at least two crystal structures and have similar orientation as that of co-crystal ligands.

Holistic management of complicated crown fracture: A case series.

Coronal fractures of the anterior teeth give an agonizing experience for a young individual due to the physical disfigurement, and the psychological impact that is imposed on them. One of the options for managing complicated/uncomplicated crown fractures when the tooth fragment is available, and there is no or minimal violation of the biological width is the rebonding of the fractured segment. This treatment approach is promising, providing good and long-lasting esthetics as it helps in maintaining the tooth's original anatomic form, hue, and surface texture. This article describes three case reports of successful reattachment of fractured tooth fragments. Following the root canal treatment procedures, prefabricated posts were cemented as intraradicular splint to reattach the fractured segments.

Ovarian Stimulation in Assisted Reproductive Technology Cycles for Varied Patient Profiles: An Indian Perspective.

Controlled ovarian stimulation has been an integral part of in vitro fertilisation (IVF) treatment cycles. Availability of different gonadotropins for ovarian stimulation and gonadotropin releasing hormone (GnRH) analogues for prevention of premature rise of leutinising hormone during follicular phase offer an opportunity to utilise them for a successful outcome in women with different subsets of ovarian response. Further, use of GnRH agonist as an alternative for human chorionic gonadotropin improves safety of ovarian stimulation in hyper-responders. Mild ovarian stimulation protocols have emerged as an alternative to conventional protocols in the recent years. Individualisation plays an important role in improving safety of IVF in hyper-responders while efforts continue to improve efficacy in poor responders. Some of the follicular and peri-ovulatory phase interventions may be associated with negative impact on the luteal phase and segmentalisation of the treatment with frozen embryo transfer may be an effective strategy in such a clinical scenario. This narrative review looks at the available evidence on various aspects of ovarian stimulation strategies and their consequences. In addition, it provides a concise summary of the evidence that has emerged from India on various aspects of ovarian stimulation.

Assessment of the factors influencing dental students to choose dentistry as a career: A cross-sectional survey.

OBJECTIVE: Career choice, one of the most important process in a student's life, has an influence on his/her future life. Hence, it is important to understand student's motives behind choosing a specific career. Hence, the study was designed with an aim to evaluate the factors influencing dental students to choose dentistry as career. METHODS: The present cross-sectional survey was conducted on 401 dental students from a dental institute. The data was collected using a structured questionnaire consisting of 13 reasons that possibly influenced students' decision to study dentistry. Data collected was analyzed using SPSS 20 software. RESULTS: Majority of the students participating were female (77.1%). Top four reasons to choose dentistry as a profession were to help poor people (95.5%), to earn prestige and respect (95.0%) followed by self-interest (94.7%) and study of human parts especially teeth (92.8%). Making money was the reason reported by 77.8% of the students. Other reasons reported were inspiration from other dentists (63.3%), did not get admission to medicine (MBBS) course (52.1%), and no doctor in family (51.9%). Family members in medical/dental profession was the least reported reason (36.9%). There were no significant differences among males and females for reported reasons except for one reason, that is, did not get admitted to medicine (MBBS) course (60.9% male and 48.9% female; P = 0.031). CONCLUSION: Students were mostly influenced by own interest and altruistic nature to opt for dental profession.

Photocatalytic activity of MnTiO3 perovskite nanodiscs for the removal of organic pollutants.

MTO nanodiscs synthesized using the hydrothermal approach were explored for the photocatalytic removal of methylene blue (MB), rhodamine B (RhB), congo red (CR), and methyl orange (MO). The disc-like structures of ~16 nm thick and ~291 nm average diameter of stoichiometric MTO were rhombohedral in nature. The MTO nanodiscs delivered stable and recyclable photocatalytic activity under Xe lamp irradiation. The kinetic studies showed the 89.7, 80.4, 79.4, and 79.4 % degradation of MB, RhB, MO, and CR at the rate constants of 0.011(±0.001), 0.006(±0.001), 0.007(±0.0007), and 0.009 (±0.0001) min-1, respectively, after the 180 min of irradiation. The substantial function of photogenerated holes and hydroxide radicals pertaining to the dye removal phenomena is confirmed by radical scavenger trapping studies. Overall, the present studies provide a way to develop pristine and heterostructure perovskite for photocatalysts degradation of various organic wastes.

Pre-Ovulatory Hormones on Day of Human Chorionic Gonadotropin Trigger and Assisted Reproductive Technique Outcomes in Different Ovarian Response Groups.

BACKGROUND: Evidence regarding impact of pre-ovulatory hormone levels on assisted reproductive technique (ART) outcomes in different ovarian response groups is sparse. AIMS: The objective of this study was to evaluate and compare the association between pre-ovulatory hormonal profile and ART outcomes in different ovarian responses. SETTING AND DESIGN: This is a single-centre retrospective cohort study of 273 non-donor fresh ART cycles between January 2013 and June 2016. MATERIALS AND METHODS: Data on clinical profile, basal and peak hormonal levels, characteristics of controlled ovarian stimulation and ART outcomes were collected. Progesterone elevation (PE) was defined as pre-ovulatory serum progesterone >1.5 ng/mL or progesterone to oestradiol ratio >1. The association between peak hormonal levels and ART outcomes in poor (≤4 oocytes retrieved), intermediate (5-13 oocytes retrieved) and high (≥14 oocytes retrieved) ovarian responders was analysed and compared. STATISTICAL ANALYSIS: Continuous and categorical variables were summarised as median (interquartile range) and percentages, respectively, and compared using Kruskal-Wallis H-test or Mann-Whitney U-test and Chi-square test or Fisher's exact test, respectively. RESULTS: The incidence of PE, by both criteria and clinical pregnancy rates (35.7%, 36.8% and 18.6% in high, normal and poor responders, respectively; P = 0.073), was similar among the three response groups. Except fertilisation rates in normo-responders, PE did not influence ART outcomes in any response group. Furthermore, there were no differences between peak hormone concentrations or incidence of PE between those who conceived and those who did not. CONCLUSION: Pre-ovulatory sex steroid levels do not seem to be the primary determinant of ART outcomes in any ovarian response category; hence, decision to freeze all embryos in the event of PE should be tailored.

Guillain-Barre Syndrome and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Secretion as Paraneoplastic Syndromes in Splenic Marginal B-cell Non-Hodgkins Lymphoma: A Rare Presentation.

Splenic marginal zone lymphoma (SMZL), a rare sub-type of non-Hodgkin lymphoma (NHL) presents with abdominal discomfort, lymphocytosis, cytopenias along with B symptoms including fatigue, night sweats, night fevers, weight loss. NHLs rarely present with paraneoplastic neurological syndromes like Guillain-Barre (GB) syndrome, myelopathy causing paraplegia, chorea, neuromyotonia, vasculitic neuropathy and dermatomyositis. Here, we present a 85-year old caucasian lady presenting with GB syndrome and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) who eventually got diagnosed with SMZL.

Joint IFS-ISAR-ACE Recommendations on Resuming/Opening up Assisted Reproductive Technology Services.

COVID-19 - A Global challenge on a scale not previously seen. Reproductive care is essential for the well-being of society and therefore the treatment needs to be completely re-thought and individualised. Infectivity and mortality rates are higher than previous pandemics and the disease is present in almost every country. Propagation and containment have varied widely by location and, at present, the timeline to complete resolution is unknown. With successful mitigation strategies in some areas and emergence of additional data, the societies have sanctioned gradual and judicious resumption of delivery of full reproductive care. When we resume, monitor local conditions, including prevalence of disease, status of government or state regulations, and availability of resource. It is important to implement proactive risk assessment within their practices prior to restarting services. One needs to develop clear and modified plans to ensure the ability to provide care while maximizing the safety of their patients and staff. One should also remain informed and stay current regarding new medical findings. These recommendations provide resources for restarting ART practice again.

BBIQ, a pure TLR7 agonist, is an effective influenza vaccine adjuvant.

Better adjuvants are needed for vaccines against seasonal influenza. TLR7 agonists are potent activators of innate immune responses and thereby may be promising adjuvants. Among the imidazoquinoline compounds, 1-benzyl-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (BBIQ) was reported to be a highly active TLR7 agonist but has remained relatively unexplored because of its commercial unavailability. Indeed, in silico molecular modeling studies predicted that BBIQ had a higher TLR7 docking score and binding free energy than imiquimod, the gold standard TLR7 agonist. To circumvent the availability issue, we developed an improved and higher yield method to synthesize BBIQ. Testing BBIQ on human and mouse TLR7 reporter cell lines confirmed it to be TLR7 specific with significantly higher potency than imiquimod. To test its adjuvant potential, BBIQ or imiquimod were admixed with recombinant influenza hemagglutinin protein and administered to mice as two intramuscular immunizations 2 weeks apart. Serum anti-influenza IgG responses assessed by ELISA 2 weeks after the second immunization confirmed that the mice that received vaccine admixed with BBIQ had significantly higher anti-influenza IgG1 and IgG2c responses than mice immunized with antigen alone or admixed with imiquimod. This confirmed BBIQ to be a TLR7-specific adjuvant able to enhance humoral immune responses.

Barriers and Opportunities of Oncofertility Practice in Nine Developing Countries and the Emerging Oncofertility Professional Engagement Network.

PURPOSE: Oncofertility practice continues to grow in developing countries despite the lack of health care services, especially those related to cancer care. The purpose of this study is to further explore oncofertility practice in these countries and identify opportunities for field-wide coalescence. METHODS: We generated a survey to learn more about oncofertility practice in nine developing countries within our Oncofertility Consortium Global Partners Network-Mexico, Colombia, Guatemala, Argentina, Chile, Nigeria, South Africa, Saudi Arabia, and India. Their responses were collected, reviewed, and discussed. RESULTS: Surveyed centers from the nine developing countries continue to experience a similar set of common challenges, including a lack of awareness among providers and patients, cultural and religious constraints, lack of insurance coverage and funding to help to support oncofertility programs, and high out-of-pocket costs for patients. Despite these barriers, many opportunities exist and there is great potential for the future. CONCLUSION: The current need is to unify the new technologies and best practices that emerge from rural communities and developing countries with those in large metropolitan cities, both domestically (US based) and abroad, into a functional unit: the Oncofertility Professional Engagement Network. The Oncofertility Professional Engagement Network will bridge the gap between domestic and international programs to establish a strong global network in which members share resources, methodologies and experiences and further build cultural competency.